Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens.

PURPOSE: To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. METHODS: In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan-Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. RESULTS: Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63-1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32-2.23]). CONCLUSION: In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.

Surgical treatment of gastric cancer liver metastases: Systematic review and meta-analysis of long-term outcomes and prognostic factors.

The prognosis of patients with metastatic gastric cancer remains dismal, with palliative treatment as standard of care. However, encouraging results have been reported for surgical resection of liver only metastatic gastric cancer in carefully selected patients. A systematic review of articles published from 2000 onwards was conducted according to PRISMA guidelines. Twenty-nine studies were included in qualitative and quantitative analysis. Meta-analysis of proportions pointed out 29.1 % 5ySR (I 2 = 39 %). The pooled weighted median of MSTs was 31.1 months. T stage > 2, metastasis greatest dimension ≥ 5 cm, the presence of multiple metastases and bilobar disease resulted among the strongest predictors of mortality. Funnel plots, Egger's tests, and P-curve analyses failed to show significant publication bias. Based on strict selection criteria and robust statistical analyses, our results show that, in very carefully selected patients without extrahepatic disease, surgical resection with curative intent may significantly improve overall survival.

Effects of abiraterone acetate plus prednisone on bone turnover markers in chemotherapy-naïve mCRPC patients after ADT failure: A prospective analysis of the italian real-world study ABITUDE.

BACKGROUND: Bone remodeling is disrupted in metastatic disease, which affects > 70% of metastatic castration-resistant prostate cancer (mCRPC) patients. As a result, abnormal levels of specific bone turnover biomarkers (BTMs) are released. In this prospective ancillary analysis of the Italian real-world study ABITUDE, four markers were measured during abiraterone acetate plus prednisone (AAP) treatment in chemotherapy-naïve mCRPC men failing androgen-deprivation therapy. METHODS: Patients were enrolled if a blood sample was obtained before the first administration of abiraterone (baseline); ad-hoc blood samples were withdrawn during routine tests after 3, 6, and 12 months. A centralized lab measured bone alkaline phosphatase (BALP, osteoblast activity marker), type-I collagen-C-telopeptide (CTX-1, bone resorption marker), parathyroid hormone (PTH) and vitamin D (vitD). At each time point, intra-patient variations vs baseline were compared by the signed-rank test (statistical significance: P-value < 0.05). RESULTS: Of 481 patients enrolled in ABITUDE, 186 (median age: 76 [range: 53-93] years) met the substudy criteria: 74.7% had bone metastases, 11.8% were on bone-targeted therapies (BTT) and 14.0% on vitD supplementation. BALP decreased significantly at month 6 (P = 0.0010) and 12 (P < 0.0001) and CTX-1 at month 6 (P = 0.0028); PTH increased at month 3 (P < 0.0001); no significant difference in vitD levels was observed. Similar findings were observed in BTT-untreated patients. The reduction in BALP and CTX-1 levels was more pronounced in patients with than without bone metastases; in the latter group, no significant variation in BALP and CTX-1 levels was observed. CONCLUSIONS: AAP seems to exert an effect on the microenvironment of metastatic but not of normal bone, which likely contributes to its antitumoral activity.

Effectiveness of abiraterone acetate plus prednisone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer in a large prospective real-world cohort: the ABItude study.

BACKGROUND: Real-world data on chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone plus prednisone are limited, largely deriving from small retrospective studies. METHODS: ABitude is an Italian, observational, prospective, multicenter study of mCRPC patients receiving abiraterone plus prednisone in clinical practice. Chemotherapy-naïve mCRPC patients were consecutively enrolled at abiraterone start (February 2016 to June 2017) and are being followed for 3 years, with evaluation approximately every 6 months. Several clinical and patients reported outcomes were examined. RESULTS: In this second interim analysis, among 481 enrolled patients, 453 were evaluable for analyses. At baseline, the median age was 77 years and ~69% of patients had comorbidities (mainly cardiovascular diseases). Metastases were located mainly at bones and lymph nodes; 8.4% of patients had visceral metastases. During a median follow-up of 18 months, 1- and 2-year probability of radiographic progression-free survival were 73.9% and 56.2%, respectively; the corresponding rates for overall survival were 87.3% and 70.4%. In multivariable analyses, the number of bone metastases significantly affected radiographic progression-free survival and overall survival. During abiraterone plus prednisone treatment, 65% of patients had a ⩾50% prostate-specific antigen decline, and quality of life remained appreciably high. Among symptomatic patients according to the Brief Pain Inventory) (32%), scores significantly declined after 6 months of treatment. Overall, eight patients (1.7%) had serious adverse reactions to abiraterone. CONCLUSIONS: Abiraterone plus prednisone is effective and safe for chemotherapy-naïve mCRPC patients in clinical practice.

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.

PURPOSE: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Discontinuation of first-line bevacizumab in metastatic colorectal cancer: the BEAWARE Italian Observational Study.

AIMS: BEAWARE investigated the pattern of first-line bevacizumab early interruption in the Italian real-world setting of metastatic colorectal cancer. METHODS: A total of 386 patients were followed for 15 months after first-line chemotherapy + bevacizumab start. The rate of bevacizumab interruption for progression or adverse drug reactions (ADRs) constituted the primary endpoint. RESULTS: A total of 78.2% of patients interrupted bevacizumab: 56.6% for progression, 7.3% for ADRs, and 36.1% for other reasons. Median treatment duration was 6.7, 2.5, and 4.6 months, respectively. Median progression-free survival was 10.3 months; however, 35.8% of patients were not progressed and were thus censored at the data cutoff of 15 months, while 21.8% were still receiving bevacizumab. Patients discontinuing for progression/ADRs more frequently had metastases in >1 site (p = .0001), and a shorter median progression-free survival (6.9 vs 13.9 months, p < .0001). CONCLUSIONS: In Italy, first-line bevacizumab is interrupted mainly for progression, only 7.3% due to adverse events, and about one third of cases for other reasons. In clinical practice, the attitude to treat until progression as per guidelines might be implemented. ClinicalTrials.gov Identifier: NCT01609075.

Efficacy and safety data in elderly patients with metastatic renal cell carcinoma included in the nivolumab Expanded Access Program (EAP) in Italy.

BACKGROUND: Results from phase III clinical trial CheckMate 025 have established nivolumab as the standard of care for treatment of metastatic renal-cell carcinoma (mRCC) after VEGF inhibitor failure; however, elderly patients are under-represented in the registration trial and little is known about the activity of nivolumab in this subgroup. The purpose of the Expanded Access Program was to provide nivolumab to patients with mRCC who had progressed despite treatment with other agents that were considered standard of care. METHODS: Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months or until progression or unacceptable toxicity. The current analysis included all patients from the EAP Italian cohort who had received ≥1 dose of nivolumab. Adverse events (AEs) were monitored using Common Terminology Criteria for Adverse Events v4.0. RESULTS: A total of 389 patients with advanced RCC were enrolled in the Italian cohort of the EAP and treated with nivolumab. Of these patients, 125 (32%) were at least 70 years of age and 70 (18%) were at least 75 years of age. Efficacy with nivolumab in the elderly patients was similar to that observed in the overall EAP population and in the CheckMate 025 trial. Safety was comparable between the elderly patients and the overall EAP population, and was consistent with what previously reported. CONCLUSION: The final results suggest that elderly patients with pretreated metastatic RCC may benefit from therapy with nivolumab.

Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma. A randomized phase III trial.

OBJECTIVE: Combination therapies of fluorouracil (FU) with irinotecan (CPT-11) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer. In this paper, we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C (MMC) monochemotherapy in an adjuvant setting. METHODS: 169 patients with radically resected gastric cancer were randomized to receive CPT-11 (180 mg/m2 day 1), leucovorin (100 mg/m2 days 1-2), FU (400-600 mg/m2 days 1-2, q 14; for four cycles; FOLFIRI regimen), followed by docetaxel (85 mg/m2 day 1), cisplatin (75 mg/m2 day 1, q 21; for three cycles; arm A), or MMC (8 mg/m2 days 1-2 as 2-hour infusion, q 42; for four cycles; arm B). All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4. A total of 166 patients (85 in arm A and 81 in arm B) were treated. Adjuvant treatment was completed in 76% of the patients in arm A and in 70% of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35%, with only 1 febrile patient, and diarrhea in 11% in arm A, and thrombocytopenia in 10% and neutropenia in 7% in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting. This sequence treatment currently represents the experimental arm of an ongoing multicenter trial.

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR).

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3'UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient's baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15-0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52-1.01, p = 0.056) in terms of PFS.

Granulocyte colony-stimulating factors used in clinical practice: PoloNord Registry-Based Cohort Italian Study.

AIMS AND BACKGROUND: Granulocyte colony-stimulating factors are widely used to reduce myelotoxicity of chemotherapy and to allow its regular administration. National and international guidelines regulate their use. The aim of the study was to evaluate the use of pegfilgrastim and filgrastim/lenograstim in clinical practice, adherence to ASCO and ESMO guidelines, chemotherapy-related complications and adverse reactions. MATERIALS AND METHODS: Data from 645 consecutive patients and 3,150 chemotherapy administrations, receiving granulocyte colony-stimulating factors, as primary/secondary prophylaxis or therapeutic use, for the first time during a line of chemotherapy, were recorded from 08/2008 to 08/2011, in 10 Lombardy Italian cancer centers. Patients and chemotherapy administrations data were examined in a multiple logistic regression analysis model. RESULTS: Adherence to guidelines: primary prophylaxis, pegfilgrastim and filgrastim/ lenograstim 66%/47% (P = 0.002); secondary prophylaxis, 19.0%/26.8%; but 56.8%/ 53.6% including patients at high risk of febrile neutropenia with grade 3-4 neutropenia. Correct timing start (administration 24-72 h after chemotherapy): pegfilgrastim and filgrastim/lenograstim, 93.2%/61.5% (P <0.0001). CONCLUSIONS: Results suggest the more correct administration of pegfilgrastim as primary prophylaxis and timing start, compared to filgrastim/lenograstim. In secondary prophylaxis, the use of granulocyte colony-stimulating factors is extended beyond guideline recommendations to support patients at high risk of febrile neutropenia and to guarantee dose intensity. These outcomes suggest both the need of educational activities and the development of predictive tools to better define high risk patients and the use of granulocyte colony-stimulating factors.

Rationale for treatment and study design of tailor: a randomized phase III trial of second-line erlotinib versus docetaxel in the treatment of patients affected by advanced non-small-cell lung cancer with the absence of epidermal growth factor receptor mutations.

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.

D-dimer before chemotherapy might predict venous thromboembolism.

To see whether D-Dimer levels can identifying patients at high risk of venous thrombotic events and establish the best benefit/risk-of-bleeding ratio. Current guidelines do not recommend routine prophylaxis against venous thromboembolism (VTE) in cancer patients receiving chemotherapy, but the risk increases about 6.5-fold because of this treatment. D-dimer was measured at baseline in 124 cancer patients scheduled for their first chemotherapy. VTE events, including symptomatic episodes of deep vein thrombosis or pulmonary embolism or both, were recorded during the first 6 months of therapy, and asymptomatic deep vein thrombosis was revealed by compression ultrasonography at baseline and after 90 and 180 days. During follow-up, there were 11 episodes of VTE (8.9%). Mean D-dimer values were higher in patients with VTE (2195 +/- 1382 vs. 695 +/- 1039 ng/ml, (P < 0.001). On grouping D-dimer values in tertiles, only 2.4% (confidence interval, 0.9-5.7%) in the first (<262 ng/ml) and second tertiles (262-650 ng/ml) suffered a deep vein thrombosis/pulmonary embolism event as compared with 22% (confidence interval, 9-34%) in the third (>650 ng/dl) (P = 0.003). The VTE-free interval was significantly shorter in the third tertile than in the first (P = 0.0218, log-rank test; relative risk for third vs. first tertile, 11.0; 95% confidence interval, 1.4-81.3; P = 0.0033). Multivariate analysis found that only baseline D-dimer concentrations were correlated with the subsequent development of VTE. Baseline D-dimer values in cancer patients scheduled for chemotherapy might be used to select those at low risk of VTE, most likely to be safe without prophylaxis.

The impact of antithrombotic prophylaxis on infectious complications in cancer patients with central venous catheters: an observational study.

Infections in cancer patients after implantation of a central venous device (CVD) are not infrequent and are potentially serious. The possibility of limiting this complication with antithrombotic drugs is still debated. For this observational study, we recorded the routine management of CVD in cancer patients in 18 oncology centers in Lombardy (northern Italy), assessing the effect of antithrombotic prophylaxis on catheter-related infections. Out of 1410 patients enrolled, 451 received antithrombotic prophylaxis continuously after implantation of the central line. During a median follow-up of 30 months, 57 catheter-related infections were reported in the 1390 patients seen at least once at follow-up visits (4.1% of the whole series), giving an overall incidence of 0.10 infections per 1000 catheter days. This complication was significantly more frequent among patients with an indwelling central venous catheter, or peripherally inserted catheter, than among those with a port device, and the group not given antithrombotic prophylaxis had 0.14 infective complications/1000 CVD days compared with 0.05/1000 CVD days (odds ratio 2.4; 95% confidence interval 1.7-5.0) for those treated. Antithrombotic prophylaxis protected against infections at the catheter exit site and track but not against systemic infections. Confirming earlier evidence, this study found a reduction in catheter-related infections in patients given antithrombotic prophylaxis. However, this reduction, reflecting local infections, seems unlikely to be one of the mechanisms explaining the lower mortality among our patients treated with anticoagulants.